Background The importance of nutritional status is underappreciated in patients with heart failure (HF). This study aimed to describe the range of the prognostic nutrition index (PNI), and the clinical characteristics and outcomes according to PNI, in patients with HF with preserved ejection fraction (HFpEF) and reduced ejection fraction (HFrEF). The primary outcome was the composite of HF hospitalization or cardiovascular death.Methods and Results Individual patient data from the PARAGON-HF (Prospective Comparison of ARNI [Angiotensin Receptor-Neprilysin Inhibitor] with ARB [Angiotensin Receptor Blocker] Global Outcomes in HFpEF) and PARADIGM-HF (Prospective Comparison of ARNI With ACEI [Angiotensin-Converting Enzyme Inhibitor] to Determine Impact on Global Mortality and Morbidity in HF) trials were used to examine patient characteristics and outcomes according to quartiles of PNI. Cox regression was used to analyze clinical outcomes, and multivariable fractional polynomial interaction analysis to examine the effects of sacubitril-valsartan, according to PNI. Patients with lower PNI (poorer nutrition) were older, frailer, and had more comorbidities and worse HF status, with greater congestion. Patients with lower PNI had biomarker abnormalities indicating inflammation, bone marrow suppression, and increased collagen turnover, among other physiologic perturbations. Lower PNI was associated with worse outcomes; that is, the rate of the primary end point among patients in the first quartile was 11.31 (10.20-12.54) compared with 7.09 (6.17-8.14) per 100 person-years in the fourth quartile. These associations persisted after adjustment for other prognostic variables. PNI did not modify the effects of sacubitril-valsartan in HFrEF although sacubitril/valsartan seemed to have a greater benefit in patients with HFpEF with a higher PNI.Conclusions Nutritional status, assessed using PNI, is an independent predictor of poor outcomes in HF. Evaluation of nutritional status in clinical practice, the causes of undernutrition, and whether undernutrition should be a therapeutic target, are all worthy of further investigation in HF.

Background and Aims An expansion of fat mass is an integral feature of patients with heart failure and preserved ejection fraction (HFpEF). While body mass index (BMI) is the most common anthropometric measure, a measure of central adiposity-the waist-to-height ratio (WHtR)-focuses on body fat content and distribution; is not distorted by bone or muscle mass, sex, or ethnicity; and may be particularly relevant in HFpEF. Methods The PARAGON-HF trial randomized 4796 patients with heart failure (HF) and ejection fraction >= 45% to valsartan or sacubitril/valsartan. The current work characterizes the association of BMI and WHtR with clinical features, outcomes, and the response to neprilysin inhibition. Results About half (49%) of the participants were considered obese by BMI (>= 30 kg/m(2)), but nearly every patient (96%) had central adiposity (WHtR >=.5). Among patients who were not obese (BMI <30 kg/m(2)), 860 (37%) had marked central adiposity (WHtR >=.6). Higher BMI and WHtR were both associated with higher risk of total HF hospitalizations, but as compared with BMI, WHtR was linearly associated with HF outcomes and identified a higher proportion of patients who had a particularly elevated risk (i.e. 30% or greater). An obesity-survival paradox (i.e. improved outcomes in those with greater adiposity) was apparent with BMI in unadjusted analyses, but it was not observed with WHtR. Although neprilysin inhibition appeared to have greater effects on HF outcomes in patients with higher BMI and WHtR, analyses of interaction with obesity metrics did not show significant heterogeneity across the range of values for adiposity. Conclusions In PARAGON-HF, in contrast with BMI, nearly every patient with HFpEF had central adiposity (as assessed by WHtR), and the risks of adverse HF events were more robustly related to WHtR. These data challenge the current reliance on BMI as an appropriate metric of adiposity, and they suggest that-rather than obesity-related HFpEF being regarded as a select HFpEF subgroup-central adiposity is a ubiquitous feature of HFpEF.

Sodium-glucose cotransporter-2 inhibitors (SGLT2i) and the nonsteroidal mineralocorticoid receptor antagonist (nsMRA) finerenone have each been shown to individually improve heart failure events among patients with heart failure and mildly reduced or preserved ejection fraction (HFmrEF/HFpEF). Moreover, the angiotensin receptor neprilysin inhibitor (ARNI) sacubitril/valsartan has been shown to improve outcomes in patients with HFmrEF/HFpEF with a left ventricular ejection fraction (LVEF) below normal (<60%). However, the expected benefits of the combined use of these agents with long-term administration are not well defined. Here, in this cross-trial analysis of DELIVER, FINEARTS-HF and PARAGON-HF, combined use of SGLT2i and nsMRA therapies was estimated to reduce the risk of cardiovascular death or first worsening heart failure event by 31% in the overall population (hazard ratio 0.69; 95% confidence interval 0.59-0.81), while combined use of SGLT2i, nsMRA and ARNI therapies was estimated to reduce risk by 39% in patients with HFmrEF/HFpEF and an LVEF <60% (hazard ratio 0.61; 95% confidence interval 0.48-0.77). With long-term use, combined SGLT2i and nsMRA therapies in a 65-year-old patient with HFmrEF/HFpEF, or combined SGLT2i, nsMRA and ARNI therapies in a 65-year-old patient with an LVEF <60%, were projected to afford 3.6 (2.0-5.2) or 4.9 (2.5-7.3) additional years free from cardiovascular death or a heart failure event, respectively. Combined therapy was estimated to result in meaningful gains in event-free survival across a broad age range, from 55 to 85 years. Among patients with HFmrEF and HFpEF, the potential aggregated long-term treatment effects of early combination medical therapy with SGLT2i and nsMRA (and ARNI in selected individuals) are projected to be substantial.

BACKGROUND:The value of generic quality of life (QoL) instruments in heart failure (HF) is uncertain. OBJECTIVES:In this study, the authors sought to quantify individual dimension scores and the EuroQol 5-Dimension questionnaire (EQ-5D) Level Sum Score (LSS) in patients with HF with reduced, mildly reduced, or preserved ejection fraction, the association between those scores and outcomes, and the impact of treatment with dapagliflozin on the scores. METHODS:Analyses were conducted using patient-level data from DAPA-HF and DELIVER trials. Cox proportional hazards regression models were used to assess the association between EQ-5D scores (each dimension and LSS) and clinical outcomes. Sankey diagrams were used to illustrate changes in individual patient EQ-5D dimensions from baseline to 8 months' follow-up. RESULTS:Of the 11,007 patients randomized in DAPA-HF and DELIVER, 10,135 (92.1%) completed the instrument at baseline. Scores varied markedly by question with 37%, 30%, and 33% of patients reporting no, slight, or moderate or greater problem, respectively for mobility; 67%, 20%, and 13% for self-care; 40%, 33%, and 27% for usual activities; 45%, 32%, and 23% for pain/discomfort; and 57%, 27%, and 16% for anxiety/depression. Patients with higher (worse) EQ-5D-LSS were more frequently female, had more comorbidities, and had worse HF status. Compared with patients free from any problem across all dimensions (ie, an EQ-5D-LSS of 5), the HRs for the composite outcome of time to first cardiovascular death or worsening HF were 1.27 (95% CI: 1.10-1.47), 1.70 (95% CI: 1.46-1.98), and 2.31 (95% CI: 1.88-2.85) in patients with EQ-5D-LSS of 6-10, 11-15, and 16-25 points, respectively. Dapagliflozin led to greater improvement and less worsening in mobility (OR: 1.13 [95% CI: 1.04-1.23]; P = 0.004), self-care (OR: 1.13 [95% CI: 1.02-1.24]; P = 0.016), usual activities (OR: 1.11 [95% CI: 1.02-1.21]; P = 0.015), and anxiety/depression (OR: 1.10 [95% CI: 1.01-1.21]; P = 0.034) after 8 months. The number needed to treat for 1 patient to report improvement in EQ-5D-LSS was 31 (95% CI: 20-72). CONCLUSIONS:The EQ-5D revealed problems not often associated (eg, pain) with HF or commonly quantified in HF (eg, anxiety/depression). Dapagliflozin improved multiple QoL dimensions, and possibly anxiety/depression. (Study to Evaluate the Effect of Dapagliflozin on the Incidence of Worsening Heart Failure or Cardiovascular Death in Patients With Chronic Heart Failure [DAPA-HF]; NCT03036124; Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure [DELIVER]; NCT03619213).

BACKGROUND:Patients with severe heart failure (HF) experience debilitating clinical symptoms and worse cardiovascular (CV) outcomes with an excess mortality risk. OBJECTIVES:The authors aimed to assess the prevalence, CV outcome risk, and treatment response to the sodium-glucose cotransporter 2 inhibitor (SGLT2i) dapagliflozin among patients with severe HF across the spectrum of left ventricular ejection fraction (LVEF) in DAPA-HF and DELIVER. METHODS:Severe HF was adapted from the ESC (European Society of Cardiology) HFA (Heart Failure Association) definition: NYHA functional class III/IV, evidence of HF with reduced, mildly reduced, or preserved LVEF, HF hospitalization within the previous 12 months, and adverse patient-reported symptom burden (Kansas City Cardiomyopathy Questionnaire-Total Symptoms Score <75). Outcomes and the treatment effect of dapagliflozin were assessed for the primary endpoint of CV death or first worsening HF event by severe HF status. RESULTS:Among 10,948 patients with available data to define severe HF, 730 (6.7%) fulfilled the severe HF definition (296/4,722 [6.2%] with LVEF ≤40%, 192/2,101 [9.1%] with LVEF 41%-49%, and 232/4,125 [5.6%] with LVEF ≥50%). Over a median follow-up of 22 months, the primary endpoint occurred in 231 patients, at a rate of 20 per 100 patient-years (Q1-Q3: 17-23 per 100 patient-years). Patients with severe HF experienced a higher rate of events than patients without severe HF (adjusted HR: 1.85; 95% CI: 1.60-2.12), regardless of LVEF (Pinteraction = 0.98). Treatment with dapagliflozin was consistently beneficial in reducing the risk of the primary endpoint regardless of severe HF status (Pinteraction = 0.48) across the LVEF spectrum (3-way Pinteraction = 0.52). The safety profile of dapagliflozin was also consistent regardless of the severe HF status. CONCLUSIONS:Severe HF was associated with an excess risk of CV events across the spectrum of LVEF. Treatment with the SGLT2i dapagliflozin appeared to be safe and effective in reducing the risk of CV death or worsening HF in this population. (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure [DAPA-HF]; NCT03036124; Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure [DELIVER]; NCT03619213).

Background Patients with heart failure with improved ejection fraction (HFimpEF) remain understudied and face residual risks comparable with those with a left ventricular ejection fraction (LVEF) consistently >40% (no prior heart failure with reduced ejection fraction). The implications of achieved LVEF after improvement on prognosis and treatment response remains unclear. Objectives This study examines whether the degree of LVEF improvement influences prognosis and the therapeutic effects of dapagliflozin in HFimpEF. Methods The DELIVER trial randomized patients with heart failure and LVEF >40% to dapagliflozin or placebo, including those with HFimpEF. In the HFimpEF subset, we examined the association between baseline LVEF (≤49% [reference group], 50%-59%, and ≥60%) and the primary outcome (worsening HF or cardiovascular death) and whether the degree of LVEF improvement modified the treatment response to dapagliflozin. Results Of 6,263 participants, 1,151 (18%) had HFimpEF: 624 (54%), 328 (29%), and 199 (17%) had improved LVEF at baseline of ≤49%, 50%-59%, and ≥60%, respectively. Over a median follow-up of 2.3 years, primary outcome rates (per 100 person-years) in HFimpEF vs LVEF consistently >40% were 9.9 vs 10.5 (≤49%), 6.7 vs 8.4 (50%-59%), and 9.3 vs 7.5 (≥60%). Dapagliflozin safely and consistently reduced the risk of the primary outcome across LVEF groups (P for interaction = 0.19). Conclusions In patients with HFimpEF, the efficacy and safety of dapagliflozin in reducing cardiovascular death or worsening HF events were consistent irrespective of the degree of LVEF improvement before enrollment, including in those who achieve an LVEF ≥60% who appear to face significant residual risks of clinical events. (Dapagliflozin Evaluation to Improve the LIVEs of Patients With Preserved Ejection Fraction Heart Failure [DELIVER]; NCT03619213)

Although several previous studies tested SGLT2 inhibitors in the setting of an acute, non-cardiovascular illness, detailed information on their efficacy and safety among participants with and without type 2 diabetes (T2D) from double-blind randomized trials is lacking. In this secondary prespecified analysis of the Dapagliflozin in Respiratory Failure in Patients with COVID-19 (DARE-19) trial, we sought to evaluate the safety and efficacy of initiating dapagliflozin during acute illness with COVID-19 in patients with and without T2D. The DARE-19 trial randomized 1250 patients hospitalized with COVID-19 and cardiometabolic risk factors to dapagliflozin or placebo. T2D was present in 636/1250 (50.9

Importance An initial decline in estimated glomerular filtration rate (eGFR) is expected after initiating a sodium-glucose cotransporter-2 inhibitor (SGLT2i) and has been observed across patients with diabetes, chronic kidney disease, and heart failure. Objective To examine the implications of initial changes in eGFR among patients with heart failure with mildly reduced ejection fraction (HFmrEF) or preserved ejection fraction (HFpEF) enrolled in the Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure (DELIVER) trial. Design, Setting, and Participants This was a prespecified analysis of the results of the DELIVER randomized clinical trial, which was an international multicenter study of patients with EF greater than 40% and eGFR greater than or equal to 25. The DELIVER trial took place from August 2018 to March 2022. Data for the current prespecified study were analyzed from February to October 2023. Intervention Dapagliflozin, 10 mg per day, or placebo. Main Outcomes and Measures In this prespecified analysis, the frequency of an initial eGFR decline (baseline to month 1) was compared between dapagliflozin and placebo. Cox models adjusted for baseline eGFR and established prognostic factors were fit to estimate the association of an initial eGFR decline with cardiovascular (cardiovascular death or heart failure event) and kidney (≥50% eGFR decline, eGFR<15 or dialysis, death from kidney causes) outcomes, landmarked at month 1, stratified by diabetes. Results Study data from 5788 participants (mean [SD] age, 72 [10] years; 3253 male [56%]) were analyzed. The median (IQR) change in eGFR level from baseline to month 1 was -1 (-6 to 5) with placebo and -4 (-9 to 1) with dapagliflozin (difference, -3; P < .001). A higher proportion of patients assigned to dapagliflozin developed an initial eGFR decline greater than 10% vs placebo (1144 of 2892 [40%] vs 737 of 2896 [25%]; odds ratio, 1.9; 95% CI, 1.7-2.1; P difference <.001). An initial eGFR decline of greater than 10% (vs ≤10%) was associated with a higher risk of the primary cardiovascular outcome among those randomized to placebo (adjusted hazard ratio [aHR], 1.33; 95% CI, 1.10-1.62) but not among those randomized to dapagliflozin (aHR, 0.90; 95% CI, 0.74-1.09; P for interaction = .01). Similar associations were observed when alternative thresholds of initial eGFR decline were considered and when analyzed as a continuous measure. An initial eGFR decline of greater than 10% was not associated with adverse subsequent kidney composite outcomes in dapagliflozin-treated patients (aHR, 0.94; 95% CI, 0.49-1.82). Conclusions and Relevance Among patients with HFmrEF or HFpEF treated with dapagliflozin, an initial eGFR decline was frequent but not associated with subsequent risk of cardiovascular or kidney events. These data reinforce clinical guidance that SGLT2is should not be interrupted or discontinued in response to an initial eGFR decline. Trial Registration ClinicalTrials.gov Identifier: NCT03619213.

AimsTo describe the baseline characteristics of participants in the FINEARTS‐HF trial, contextualized with prior trials including patients with heart failure (HF) with mildly reduced and preserved ejection fraction (HFmrEF/HFpEF). The FINEARTS‐HF trial is comparing the effects of the non‐steroidal mineralocorticoid receptor antagonist finerenone with placebo in reducing cardiovascular death and total worsening HF events in patients with HFmrEF/HFpEF.Methods and resultsPatients with symptomatic HF, left ventricular ejection fraction (LVEF) ≥40%, estimated glomerular filtration rate ≥ 25 ml/min/1.73 m2, elevated natriuretic peptide levels and evidence of structural heart disease were enrolled and randomized to finerenone titrated to a maximum of 40 mg once daily or matching placebo. We validly randomized 6001 patients to finerenone or placebo (mean age 72 ± 10 years, 46% women). The majority were New York Heart Association functional class II (69%). The baseline mean LVEF was 53 ± 8% (range 34–84%); 36% of participants had a LVEF <50% and 64% had a LVEF ≥50%. The median N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP) was 1041 (interquartile range 449–1946) pg/ml. A total of 1219 (20%) patients were enrolled during or within 7 days of a worsening HF event, and 3247 (54%) patients were enrolled within 3 months of a worsening HF event. Compared with prior large‐scale HFmrEF/HFpEF trials, FINEARTS‐HF participants were more likely to have recent (within 6 months) HF hospitalization and greater symptoms and functional limitations. Further, concomitant medications included a larger percentage of sodium–glucose cotransporter 2 inhibitors and angiotensin receptor–neprilysin inhibitors than previous trials.ConclusionsFINEARTS‐HF has enrolled a broad range of high‐risk patients with HFmrEF and HFpEF. The trial will determine the safety and efficacy of finerenone in this population.

Importance:Accurate risk prediction of morbidity and mortality in patients with heart failure with preserved ejection fraction (HFpEF) may help clinicians risk stratify and inform care decisions. Objective:To develop and validate a novel prediction model for clinical outcomes in patients with HFpEF using routinely collected variables and to compare it with a biomarker-driven approach. Design, Setting, and Participants:Data were used from the Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure (DELIVER) trial to derive the prediction model, and data from the Angiotensin Receptor Neprilysin Inhibition in Heart Failure With Preserved Ejection Fraction (PARAGON-HF) and the Irbesartan in Heart Failure With Preserved Ejection Fraction Study (I-PRESERVE) trials were used to validate it. The outcomes were the composite of HF hospitalization (HFH) or cardiovascular death, cardiovascular death, and all-cause death. A total of 30 baseline candidate variables were selected in a stepwise fashion using multivariable analyses to create the models. Data were analyzed from January 2023 to June 2023. Exposures:Models to estimate the 1-year and 2-year risk of cardiovascular death or hospitalization for heart failure, cardiovascular death, and all-cause death. Results:Data from 6263 individuals in the DELIVER trial were used to derive the prediction model and data from 4796 individuals in the PARAGON-HF trial and 4128 individuals in the I-PRESERVE trial were used to validate it. The final prediction model for the composite outcome included 11 variables: N-terminal pro-brain natriuretic peptide (NT-proBNP) level, HFH within the past 6 months, creatinine level, diabetes, geographic region, HF duration, treatment with a sodium-glucose cotransporter 2 inhibitor, chronic obstructive pulmonary disease, transient ischemic attack/stroke, any previous HFH, and heart rate. This model showed good discrimination (C statistic at 1 year, 0.73; 95% CI, 0.71-0.75) in both validation cohorts (C statistic at 1 year, 0.71; 95% CI, 0.69-0.74 in PARAGON-HF and 0.75; 95% CI, 0.73-0.78 in I-PRESERVE) and calibration. The model showed similar discrimination to a biomarker-driven model including high-sensitivity cardiac troponin T and significantly better discrimination than the Meta-Analysis Global Group in Chronic (MAGGIC) risk score (C statistic at 1 year, 0.60; 95% CI, 0.58-0.63; delta C statistic, 0.13; 95% CI, 0.10-0.15; P < .001) and NT-proBNP level alone (C statistic at 1 year, 0.66; 95% CI, 0.64-0.68; delta C statistic, 0.07; 95% CI, 0.05-0.08; P < .001). Models derived for the prediction of all-cause and cardiovascular death also performed well. An online calculator was created to allow calculation of an individual's risk. Conclusions and Relevance:In this prognostic study, a robust prediction model for clinical outcomes in HFpEF was developed and validated using routinely collected variables. The model performed better than NT-proBNP level alone. The model may help clinicians to identify high-risk patients and guide treatment decisions in HFpEF.

BACKGROUND AND AIMS:Individuals with heart failure (HF), other forms of cardiovascular disease, or kidney disease are at increased risk for the development and adverse health effects of diabetes. As such, prevention or delay of diabetes is an important treatment priority in these groups. The aim of this meta-analysis was to determine the effect of sodium-glucose co-transporter 2 inhibitors (SGLT2i) on incident diabetes in HF across the spectrum of left ventricular ejection fraction (LVEF) and across the broader spectrum of cardiovascular or kidney disease. METHODS:First, the effects of dapagliflozin vs. placebo on new-onset diabetes were assessed in a pooled, participant-level analysis of the DAPA-HF and DELIVER trials. New-onset diabetes was defined as the new initiation of glucose-lowering therapy during follow-up, and time from randomization to new-onset diabetes was evaluated using Cox proportional hazards models. Second, PubMed and Embase were searched to identify large-scale randomized clinical outcomes trials (RCTs) comparing SGLT2i with placebo among adults with cardiovascular or kidney disease. A trial-level meta-analysis was then conducted to summarize the treatment effects of SGLT2i on the incidence of new-onset diabetes. RESULTS:In the pooled analysis of DAPA-HF and DELIVER including 5623 participants with HF but without diabetes at baseline, dapagliflozin reduced the incidence of new-onset diabetes by 33% [hazard ratio (HR), 0.67; 95% confidence interval (CI), .49-.91; P = .012] when compared with placebo. There was no evidence of heterogeneity across the spectrum of continuous LVEF or key subgroups. Among seven complementary RCTs including 17 855 participants with cardiovascular or kidney disease, SGLT2i reduced the of new-onset diabetes by 26% (HR, 0.74; 95% CI .65-.85; P < .001), with consistent effects across trials. CONCLUSIONS:SGLT2i reduced the incidence of new-onset diabetes among individuals with cardiovascular or kidney disease. These findings suggest that SGLT2i implementation may have an important ancillary benefit on prevention or delay of diabetes in these high-risk populations.

Aims Although much is known about the usefulness of heart failure (HF)-specific instruments for assessing patient well-being, less is known about the value of generic instruments for the measurement of health-related quality of life (HRQL) in HF. The aim of this study was to assess the relationship between the EuroQol 5-dimension 5-level (EQ-5D-5L) visual analogue scale (VAS) and index scores, clinical characteristics, and outcomes in patients with HF and the effect of dapagliflozin on these scores. Methods and results We performed a patient-level pooled analysis of the DAPA-HF and DELIVER trials, which investigated the effectiveness and safety of dapagliflozin in patients with HF and reduced ejection fraction (HFrEF) and mildly reduced/preserved ejection fraction (HFmrEF/HFpEF), respectively. Patients reporting higher (better) EQ-5D-5L VAS and index scores had a lower prevalence of comorbidities, including atrial fibrillation and hypertension, than patients with a worse score. They were also more likely to have better investigator-reported (New York Heart Association class) and patient-self-reported (Kansas City Cardiomyopathy Questionnaire) health status and lower median N-terminal pro-B-type natriuretic peptide levels. Compared to patients with the lowest scores (Q1), those with higher EQ-5D-5L VAS scores had better outcomes: the hazard ratio for the composite of cardiovascular death or worsening HF was 0.81 (95% confidence interval 0.72-0.91) in Q2, 0.74 (0.65-0.84) in Q3, and 0.62 (0.54-0.72) in Q4. The risk of each component of the composite outcome, and all-cause death, was also lower in patients with better scores. Similar findings were observed for the index score. Treatment with dapagliflozin improved both EQ-5D-5L VAS and index scores across the range of ejection fraction. Conclusions Both higher (better) EQ-5D-5L VAS and index scores were associated with better outcomes. Dapagliflozin treatment improved EQ-5D-5L VAS and index scores, irrespective of ejection fraction.

AIMS:Patients with heart failure (HF) with improved ejection fraction (HFimpEF) may face residual risks of clinical events that are comparable to those experienced by patients with HF whose left ventricular ejection fraction (LVEF) has consistently been above 40%. However, little is known about the clinical course of patients with HFimpEF during hospitalization for HF. METHODS AND RESULTS:DELIVER randomized patients with HF and LVEF >40% to dapagliflozin or placebo, including HFimpEF (LVEF previously ≤40%). We evaluated all HF hospitalizations adjudicated by the clinical endpoints committee with available data for determination of in-hospital course. Complicated hospitalization was defined as any hospitalization requiring intensive care unit stay, intravenous vasopressors/inotropes/vasodilators, invasive or non-invasive ventilation, mechanical fluid removal, ultrafiltration, or mechanical circulatory support. LVEF changes were extracted using a validated GPT-3.5, a large language model, via a secure private endpoint. Of the 6263 patients enrolled in DELIVER, 1151 (18%) had HFimpEF. During a median follow-up of 2.3 years, there were 224 total HF hospitalizations in 144 patients with HFimpEF and 985 in 603 patients with LVEF consistently >40%. Patients with HFimpEF experienced higher rates of complicated HF hospitalization as compared with patients with LVEF consistently >40% (39% vs. 27%; p < 0.001). Among those who experienced a first HF hospitalization, there was no significant difference in length of stay or in-hospital mortality between patients with HFimpEF versus LVEF consistently >40%. In a subset of participants who had at least one LVEF measurement available during HF hospitalization, 66% of those with HFimpEF and 29% of patients with LVEF consistently >40% experienced a reduction in their LVEF to ≤40% from the time of enrolment (p < 0.001). In the entire DELIVER cohort, dapagliflozin reduced total uncomplicated and complicated HF hospitalizations, irrespective of HFimpEF status (pinteraction ≥0.30). CONCLUSIONS:Among patients hospitalized for HF in DELIVER, those with HFimpEF experienced a more adverse in-hospital clinical course, necessitating higher resource utilization beyond standard diuretic therapy compared with patients with HF and LVEF consistently >40%, but had similar in-hospital mortality. Treatment benefits of dapagliflozin were not modified by hospitalization type.

BACKGROUND:Cognitive impairment is common in patients with heart failure and preserved ejection fraction but its clinical correlates and prognostic associations are poorly understood. METHODS:We analyzed cognitive function, using the Mini-Mental State Examination (MMSE), in patients with heart failure and preserved ejection fraction enrolled in a prespecified substudy of the PARAGON-HF trial (Prospective Comparison of Angiotensin Receptor Neprilysin Inhibitor With Angiotensin Receptor Blocker Global Outcomes in Heart Failure With Preserved Ejection Fraction). Logistic regression analyses were performed to determine the variables associated with lower MMSE scores at baseline and postbaseline decline in MMSE scores at 48 weeks. Cox proportional hazards regression and semiparametric proportional rates models were used to examine the risk of clinical outcomes related to baseline MMSE scores, and decline in MMSE scores during follow-up, adjusted for prognostic variables including NT-proBNP (N-terminal pro-B-type natriuretic peptide). RESULTS:At baseline, cognitive function was normal (MMSE score 28-30) in 1809 of 2895 patients (62.5%), borderline (score 24-27) in 794 (27.4%), and impaired (score <24) in 292 (10.1%). Variables associated with both a lower MMSE score at baseline and a decline in score from baseline included older age, a history of stroke or transient ischemic attack, and lower serum albumin. Compared with those with baseline MMSE scores of 28 to 30, patients in the lower MMSE score categories had a stepwise increase in the risk of the composite of time to first heart failure hospitalization or cardiovascular death, with an adjusted hazard ratio of 1.27 (95% CI, 1.06-1.53) for those with scores of 24 to 27 and 1.58 (95% CI, 1.21-2.06) for those with scores <24, respectively. These associations were also found for the individual components of the composite and all-cause death. Likewise, cognitive impairment was associated with a 50% higher risk of total (first and repeat) heart failure hospitalizations and cardiovascular deaths. Examining the change in MMSE score from baseline, a decrease in MMSE score during follow-up was associated with a higher risk of death. CONCLUSIONS:In patients with heart failure and preserved ejection fraction, even modest baseline impairment of cognitive function was associated with worse outcomes, including death. A decline in MMSE score during follow-up was a strong predictor of mortality, independent of other prognostic variables.

AIMS:Although the prevalence of heart failure (HF) increases markedly with advancing age, surprisingly little is known about HF in the very elderly. The aim of this study was to describe the clinical characteristics and outcomes of octogenarians with HF. METHODS AND RESULTS:Individual participant meta-analysis of patients with HF and reduced, mildly reduced, and preserved ejection fraction (HFrEF, HFmrEF, and HFpEF, respectively) enrolled in eight large randomized trials. Overall, the proportion of octogenarians was 1518 of 20 168 patients (7.5%) with HFrEF, 610 of 4609 (13.2%) with HFmrEF, and 3130 of 15 354 (20.4%) with HFpEF. Regardless of HF phenotype, octogenarian patients were more often female and had more comorbidities, more symptoms and signs of congestion, and worse health status (but not quality of life), in comparison to patients aged <80 years. The incidence (per 100 person-years) of the composite of cardiovascular death or HF hospitalization was 13.3 (95% confidence interval [CI] 12.7-14.0) in octogenarians versus 9.5 (95% CI 9.3-9.7) in non-octogenarians (adjusted hazard ratio [aHR] 1.40, 95% CI 1.32-1.48). Each component of the composite was more frequent in octogenarians with rates of cardiovascular mortality of 7.0 (95% CI 6.5-7.4) per 100 person-years versus 4.9 (95% CI 4.8-5.1) in non-octogenarians (aHR 1.60, 95% CI 1.48-1.72, p < 0.001). Octogenarians received less evidence-based therapy, especially mineralocorticoid receptor antagonists, than younger patients. CONCLUSION:Despite worse health status and higher hospitalization and mortality rates, octogenarians were undertreated compared to younger patients.

ImportanceAn initial decline in estimated glomerular filtration rate (eGFR) is expected after initiating a sodium-glucose cotransporter-2 inhibitor (SGLT2i) and has been observed across patients with diabetes, chronic kidney disease, and heart failure.ObjectiveTo examine the implications of initial changes in eGFR among patients with heart failure with mildly reduced ejection fraction (HFmrEF) or preserved ejection fraction (HFpEF) enrolled in the Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure (DELIVER) trial.Design, Setting, and ParticipantsThis was a prespecified analysis of the results of the DELIVER randomized clinical trial, which was an international multicenter study of patients with EF greater than 40% and eGFR greater than or equal to 25. The DELIVER trial took place from August 2018 to March 2022. Data for the current prespecified study were analyzed from February to October 2023.InterventionDapagliflozin, 10 mg per day, or placebo.Main Outcomes and MeasuresIn this prespecified analysis, the frequency of an initial eGFR decline (baseline to month 1) was compared between dapagliflozin and placebo. Cox models adjusted for baseline eGFR and established prognostic factors were fit to estimate the association of an initial eGFR decline with cardiovascular (cardiovascular death or heart failure event) and kidney (≥50% eGFR decline, eGFR<15 or dialysis, death from kidney causes) outcomes, landmarked at month 1, stratified by diabetes.ResultsStudy data from 5788 participants (mean [SD] age, 72 [10] years; 3253 male [56%]) were analyzed. The median (IQR) change in eGFR level from baseline to month 1 was −1 (−6 to 5) with placebo and −4 (−9 to 1) with dapagliflozin (difference, −3; P < .001). A higher proportion of patients assigned to dapagliflozin developed an initial eGFR decline greater than 10% vs placebo (1144 of 2892 [40%] vs 737 of 2896 [25%]; odds ratio, 1.9; 95% CI, 1.7-2.1; P difference <.001). An initial eGFR decline of greater than 10% (vs ≤10%) was associated with a higher risk of the primary cardiovascular outcome among those randomized to placebo (adjusted hazard ratio [aHR], 1.33; 95% CI, 1.10-1.62) but not among those randomized to dapagliflozin (aHR, 0.90; 95% CI, 0.74-1.09; P for interaction = .01). Similar associations were observed when alternative thresholds of initial eGFR decline were considered and when analyzed as a continuous measure. An initial eGFR decline of greater than 10% was not associated with adverse subsequent kidney composite outcomes in dapagliflozin-treated patients (aHR, 0.94; 95% CI, 0.49-1.82).Conclusions and RelevanceAmong patients with HFmrEF or HFpEF treated with dapagliflozin, an initial eGFR decline was frequent but not associated with subsequent risk of cardiovascular or kidney events. These data reinforce clinical guidance that SGLT2is should not be interrupted or discontinued in response to an initial eGFR decline.Trial RegistrationClinicalTrials.gov Identifier: NCT03619213

AimsType 2 diabetes (T2D) and heart failure (HF) frequently coexist, but whether clinical outcomes and treatment effects of sodium–glucose cotransporter 2 inhibitors (SGLT2i) vary in relation to background glucose‐lowering therapy (GLT) in this population is uncertain.Methods and resultsDELIVER randomized patients with HF and left ventricular ejection fraction (LVEF) >40% to dapagliflozin or placebo. The primary outcome was a composite of worsening HF (HF hospitalization or urgent HF visit) or cardiovascular death. In this pre‐specified analysis of participants with T2D, treatment effects were assessed by number and class of background GLT(s). Of 3150 participants with T2D at baseline, 22.9% were on no GLT, 36.5% were treated with 1 GLT, and 40.6% with ≥2 GLTs. During follow‐up (median: 2.3 years), treatment benefits of dapagliflozin (vs. placebo) on the primary outcome were consistent irrespective of the number of background GLTs (0 GLTs: hazard ratio [HR] 0.71, 95% confidence interval [CI] 0.50–1.00; 1 GLT: HR 1.04, 95% CI 0.80–1.34; ≥2 GLTs: HR 0.71, 95% CI 0.56–0.90; pinteraction = 0.59). Similar findings were observed among participants with (HR 0.73, 95% CI 0.59–0.92) and without background metformin use (HR 0.89, 95% CI 0.72–1.11; pinteraction = 0.22) and in participants with (HR 0.89, 95% CI 0.69–1.16) and without background insulin use (HR 0.78, 95% CI 0.65–0.95; pinteraction = 0.45). Dapagliflozin was well‐tolerated irrespective of the number of background GLTs.ConclusionsDapagliflozin safely and consistently improved clinical outcomes among individuals with T2D and HF with LVEF >40% irrespective of the number and class of background GLTs, and the benefits were not influenced by concomitant metformin or insulin use. These data bolster contemporary guidelines supporting first‐line SGLT2i among individuals with T2D and HF, irrespective of background GLT.

Background: Patients with severe heart failure (HF) experience debilitating clinical symptoms and worse cardiovascular (CV) outcomes with an excess mortality risk. Until recently, severe HF has largely been considered only in those with reduced ejection fraction. The ESC HFA has put forth a consensus definition for severe or advanced HF that may be applicable across the ejection fraction (EF) spectrum. Hypothesis: Patients with severe HF experience a higher rate of CV outcomes. The safety and efficacy of SGLT2i dapagliflozin is consistent regardless of the severe HF status. Aims: To assess the prevalence, CV outcome risk, and treatment response to the SGLT2i dapagliflozin among patients with severe HF. Methods: DAPA-HF and DELIVER were randomized, double-blind trials, testing dapagliflozin vs placebo in 11,007 patients with symptomatic HF across the full spectrum of EF. Severe HF was adapted from the ESC HFA definition: NYHA class III/IV, evidence of HF with reduced, mildly reduced or preserved EF, elevated natriuretic peptides, HF hospitalization within previous 12 months, and adverse patient-reported symptom burden (KCCQ-TSS<75). Outcomes were assessed and the treatment effect of dapagliflozin was measured for the primary endpoint of CV death or first worsening HF event (including HF hospitalization and urgent HF visit) by severe HF status. Results: Overall, 730 (6.6%) fulfilled the severe HF definition (296 [40.6%] with EF ≤40%, 192 [26.3%] with EF 41-49%, and 232 [33.2%] with EF ≥50%). Patients with severe HF had a higher comorbidity burden and higher NT-proBNP values. Over a median follow-up of 22.4 months, the primary endpoint occurred in 231 patients, at a rate of 20 (17-23) per 100py. Patients with severe HF experienced a higher rate of events compared to patients without severe HF (adjusted hazard ratio [HR] 1.44, 95% confidence interval [CI] 1.20-1.75), across the spectrum of LVEF (P interaction =0.85). Treatment with dapagliflozin was consistently beneficial in reducing the risk of the primary endpoint regardless of the severe HF status (P interaction =0.10, Figure 1 ). The safety profile of dapagliflozin was also consistent irrespective of the severe HF status ( Figure 2 ). Conclusions: In a large, global contemporary HF trial population, “severe HF” was associated with excess risk of CV events across the spectrum of EF. Treatment with the SGLT2i dapagliflozin appears safe and effective in reducing the risk of CV death or worsening HF in this population.

BACKGROUND: A hypothetical concern has been raised that sacubitril/valsartan might cause cognitive impairment because neprilysin is one of several enzymes degrading amyloid-β peptides in the brain, some of which are neurotoxic and linked to Alzheimer-type dementia. To address this, we examined the effect of sacubitril/valsartan compared with valsartan on cognitive function in patients with heart failure with preserved ejection fraction in a prespecified substudy of PARAGON-HF (Prospective Comparison of Angiotensin Receptor Neprilysin Inhibitor With Angiotensin Receptor Blocker Global Outcomes in Heart Failure With Preserved Ejection Fraction). METHODS: In PARAGON-HF, serial assessment of cognitive function was conducted in a subset of patients with the Mini-Mental State Examination (MMSE; score range, 0–30, with lower scores reflecting worse cognitive function). The prespecified primary analysis of this substudy was the change from baseline in MMSE score at 96 weeks. Other post hoc analyses included cognitive decline (fall in MMSE score of ≥3 points), cognitive impairment (MMSE score <24), or the occurrence of dementia-related adverse events. RESULTS: Among 2895 patients included in the MMSE substudy with baseline MMSE score measured, 1453 patients were assigned to sacubitril/valsartan and 1442 to valsartan. Their mean age was 73 years, and the median follow-up was 32 months. The mean±SD MMSE score at randomization was 27.4±3.0 in the sacubitril/valsartan group, with 10% having an MMSE score <24; the corresponding numbers were nearly identical in the valsartan group. The mean change from baseline to 96 weeks in the sacubitril/valsartan group was −0.05 (SE, 0.07); the corresponding change in the valsartan group was −0.04 (0.07). The mean between-treatment difference at week 96 was −0.01 (95% CI, −0.20 to 0.19; P =0.95). Analyses of a ≥3-point decline in MMSE, decrease to a score <24, dementia-related adverse events, and combinations of these showed no difference between sacubitril/valsartan and valsartan. No difference was found in the subgroup of patients tested for apolipoprotein E ε4 allele genotype. CONCLUSIONS: Patients with heart failure with preserved ejection fraction in PARAGON-HF had relatively low baseline MMSE scores. Cognitive change, measured by MMSE, did not differ between treatment with sacubitril/valsartan and treatment with valsartan in patients with heart failure with preserved ejection fraction. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01920711.